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Benefits of curcumin in brain disorders

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DOI: 10.1002/biof.1533

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Received: 12 April 2019 Accepted: 22 May 2019
DOI: 10.1002/biof.1533

REVIEW ARTICLE

Benefits of curcumin in brain disorders

Abid Bhat1,2 | Arehally M. Mahalakshmi1,2 | Bipul Ray1,2 | Sunanda Tuladhar1,2 |

Tousif A. Hediyal1 | Esther Manthiannem1 | Jagadeeswari Padamati1 |
Ramesh Chandra3,4 | Saravana B. Chidambaram1,2 | Meena K. Sakharkar5

1
Department of Pharmacology, JSS College
of Pharmacy, JSS Academy of Higher
Abstract
Education & Research, Mysuru, India Curcumin is widely consumed in Asia either as turmeric directly or as one of the
2
Central Animal Facility, JSS Academy of culinary ingredients in food recipes. The benefits of curcumin in different organ sys-
Higher Education & Research, Mysuru,
tems have been reported extensively in several neurological diseases and cancer.
India
3
Drug Discovery & Development
Curcumin has got its global recognition because of its strong antioxidant, anti-
Laboratory, Department of Chemistry, inflammatory, anti-cancer, and antimicrobial activities. Additionally, it is used in dia-
University of Delhi, Delhi, India betes and arthritis as well as in hepatic, renal, and cardiovascular diseases. Recently,
4
Dr. B. R. Ambedkar Centre for Biomedical
there is growing attention on usage of curcumin to prevent or delay the onset of neu-
Research University of Delhi, Delhi, India
5 rodegenerative diseases. This review summarizes available data from several recent
College of Pharmacy and Nutrition,
University of Saskatchewan, Saskatoon, studies on curcumin in various neurological diseases such as Alzheimer's disease,
Saskatchewan, Canada Parkinson's disease, Multiple Sclerosis, Huntington's disease, Prions disease, stroke,

Correspondence
Down's syndrome, autism, Amyotrophic lateral sclerosis, anxiety, depression, and
Dr. Saravana Babu Chidambaram, PhD, aging. Recent advancements toward increasing the therapeutic efficacy of cur-
Associate Professor, Department of cuma/curcumin formulation and the novel delivery strategies employed to overcome
Pharmacology JSS College of Pharmacy &
Central Animal Facility, JSS AHER, its minimal bioavailability and toxicity studies have also been discussed. This review
Mysuru, Karnataka 570015, India. also summarizes the ongoing clinical trials on curcumin for different neurodegenera-
Email: csaravanababu@gmail.com;
tive diseases and patent details of curcuma/curcumin in India.
babupublications@gmail.com
Dr Meena Kishore Sakharkar, PhD,
KEYWORDS
Associate Professor, College of Pharmacy
and Nutrition, University of Saskatchewan, bioavailability, clinical trials, curcumin, neurodegenerative diseases, patents
107, Wiggins Road, Saskatoon,
Saskatchewan, Canada S7N 5C9.
Email: meena.sakharkar@usask.ca

1 | INTRODUCTION
Abbreviations: AD, Alzheimer's disease; ALS, amyotrophic lateral
sclerosis; ASD, autism spectrum disorder; AUC, area under the curve; Aβ, Curcuma longa, commonly known as turmeric, is a perennial
amyloid beta; BBB, blood–brain barrier; BCS, biopharmaceutics
herb that belongs to Zingiberaceae family with 133 different
classification system; BDNF, brain-derived neurotrophic factor; GFAP, glial
fibrillary acidic protein; HD, Huntington's disease; MBP, myelin basic species available worldwide. Turmeric is commonly called as
protein; MMP, mitochondrial membrane potential; MPTP, 1-methyl- “golden spice” or “spice of life”.1 Curcuma has been reported
4-phenyl-1,2,3,6-tetrahydropyridine; NOAEL, no observed adverse effect to be used in Ayurveda, Siddha, and Unani system of medi-
level; PD, Parkinson's disease; PLGA, poly(lactic-co-glycolic acid); PPAR-γ, cines from Vedic times. Turmeric also has special religious
peroxisome proliferator-activated receptor gamma; ROS, reactive oxygen
species; scNB, scrapie-infected neuroblastoma; SMA, spinal muscular
significance in Hinduism. It is used as a cooking spice,
atrophy; SMN1, survival motor neuron 1; SNpc, substantia nigra compacta; cosmetic agent, dying agent, and also in medicinal practice
TIA, transient ischemic attack. to treat various ailments like skin infections and liver

© 2019 International Union of Biochemistry and Molecular Biology

BioFactors. 2019;1–24. wileyonlinelibrary.com/journal/biof 1

2 BHAT ET AL.

and gastrointestinal disorders.2 In Asian countries, an individ- 3 | S T R U C T U R E OF C U R C U M I N

ual's consumption of turmeric has been estimated to be
200–1,000 mg per day,3 while in India, its average consump- The chemical structure of curcumin shows symmetry to
tion is estimated to be about 4 g/day.4 Average quantity of tur- molecule formula C21H20O6 (1E,6E): 1,7-bis(4-hydroxy-
meric intake in urban population to be reported lower 3-methoxyphenyl)-1,6-heptadiene-3,5-dione, with molecular
than compared to rural population (0.73 g/day)5 and low weight of 368.38 g/mol. This molecule has three functional
(0.25 g/day) in high economic strata versus low economic groups attached in its structure: o-Methoxy phenolic groups pre-
strata (0.49 g/day). Curcumin content in turmeric of turmeric is sent in the two aromatic ring systems, associated with a seven
variable. The percentage has been estimated to be between carbon attachment comprising α, β-unsaturated β-diketone
1.06% and 5.70% in four different commercially available tur- group, which show keto-enol tautomerism.11 Turmeric contains
meric samples.6 Therapeutic contributions of curcumin in 2–9% curcuminoids, depending upon its biological origin and
soil fertility and its place of cultivation. Curcuminoids include
many neurological diseases have been proven in several
compounds like curcumin (77%), demethoxycurcumin (17%),
studies.7–9 Lower incidence rate of many neurodegenerative
and bis-demethoxycurcumin (3%).18 The principal constituent is
diseases in Indians can be attributed to the regular intake of tur-
curcumin while cyclic curcumin is the minor constituent11
meric in their routine diet.5
(Figure 1).

2 | CURCUMIN 3.1 | Synthesis of curcumin

Chemical synthesis of pure curcumin began with chemist
In 1815, Vogel and Pelletier made the remarkable scientific
Lampe. He synthesized curcumin using carbomethoxy fer-
discovery of curcumin by isolating the yellow colored pig- uloyl chloride and ethyl acetoacetate.19 Later, Pabon (2010)
ment from the rhizomes of turmeric. They synthesized pure developed a new preparatory process of curcumin using
curcumin in 1842. Roughly and Whiting described its chemi- acetylacetone and substituted aromatic aldehydes in the
cal structure detail later in 197310. Up until the end of the presence of boron trioxide (B2O3), trialkyl borate, and
twentieth century, the biological significance of curcumin was n-butylamine and then stabilized the preparatory method
not investigated. Later, chemists discovered that turmeric with some minor modifications. Pabon's preparatory method
paper can be used to test the alkalinity of substance, as the tur- has been used extensively and has a good yield. In this
meric's orange-yellow root powder color changed into reddish method, 2,4-diketones reacts with substituted aromatic alde-
brown color when treated with alkaline chemicals. Both hydes and undergoes Knoevenagel condensation with boron
Americans and Europeans had little interest in curcumin. complex to avoid precipitation. In anhydrous environment,
Great enthusiasm in curcumin research started after curcumin gets separated easily using polar aprotic solvents.
researchers came to know about the botanical history of
Curcuma longa from the book, “Maude Greve's book—A
Modern Herbal”. Though various Indian medical systems use
turmeric from ancient times, German scientists started detailed
research in early 1920s, as they identified the therapeutic
potential of oils extracted from the roots of Curcuma herb in
1926. Curcumin is extracted from turmeric by column chro-
matography, soxhlet apparatus, pulse ultrasonic, and
microwave-based extraction methods.11 It is known to exhibit
antioxidant, anti-inflammatory,12 anti-cancer,13 and antimicro-
bial activities14 because of which it has attained global recog-
nition. Additionally, it is used in diabetes and arthritis as well
as in hepatic, renal, and cardiovascular diseases.15 Even
though, several animal models and human clinical trials have
confirmed the high safety index of curcumin, its fundamental
limitation is its poor bioavailability.16 Curcumin has been
reported to have a low absorption rate, high biotransformation
rate in intestines, and fast elimination rate from the systemic
circulation.17 FIGURE 1 Chemical structure of curcumin
BHAT ET AL. 3

Primary and secondary amines act as catalytic agents by pro- 5 | CURCUMIN IN

viding the required basicity to deprotonate the alkyl groups NEURODEGENERATIVE DISEASES
of the diketone. Excess water formed during the process of
condensation with diketone complex is removed using alkyl Curcumin is a pleiotropic molecule, which not only directly
borates. Under mild acidic environment, the boron complex binds to and limits aggregation of misfolded proteins in
breaks into curcumin that can be separated by washing con- many neurodegenerative diseases but also maintains homeo-
tinuously and precipitated by column chromatography.20 stasis of the inflammatory system, enhances the clearance of
toxic aggregates from the brain, scavenges free radicals, che-
lates iron, and induces anti-oxidant response elements.
4 | BIOPHARMACEUTICAL Although curcumin corrects dysregulation of several path-
CLA SSIFICA T I ON SYST E M : ways, it may exert multiple effects via a few molecular tar-
CURCUMIN gets.23 Curcumin is a drug of interest in the management of
various neurodegenerative discussed below (Figure 2).
Biopharmaceutics classification system (BCS) is a valuable
tool that provides important details about the development
5.1 | Alzheimer's disease
of a formulation as per biopharmaceutical rules. As per
BCS, drugs are classified into four classes based on their Alzheimer's disease (AD) is a fatal neurodegenerative disease.
individual solubility and intestinal permeability. Drugs in It is characterized by the presence of neurofibrillary tangles
Class I have high solubility/high permeability, Class II sub- extracellularly and senile plaques intracellularly along with
stances have low solubility/high permeability, Class III progressive loss of neurons and dendritic spines in the hippo-
drug substances have high solubility/low permeability, and campal and cortical regions. This results in abnormal neural
Class IV drug substances have low solubility/low perme- circuitry and synaptic loss.24,25 The most important symptoms
ability. A drug is classified as “highly permeable” when its in AD include decline in cognitive and motor performances,
extent of absorption is found to be above 90% upon admin- dementia and memory loss.26 Accumulation of insoluble
istration of single dose.21 Curcumin falls under BCS class alpha-beta amyloid protein leads to senile plagues and hyper-
IV category due to its limited solubility in aqueous solvents phosphorylation of tau proteins at multiple sites results in
(11 mg/mL in aqueous buffer pH 5) and low penetrability neurofibrillary tangles.27 Both plaques and tangles form the
through intestinal epithelial cells.22 Poor solubility and bio- basic pathology of neuroinflammation. Senile plaques and
availability of curcumin significantly affect its therapeutic amyloid fibrils form chaperone protein plaques that damage
application. the neuronal structure and its synaptic connections.26

FIGURE 2 A summary of molecular mechanism of action of curcumin in different neurodegenerative diseases

4 BHAT ET AL.

Curcumin, because of its strong anti-inflammatory activity, that curcumin significantly protects TH positive cells in
binds with Aβ (Amyloid beta), and prevents protein aggrega- the substantia nigra and restores the dopamine levels in the
tion and also destabilize the preformed fibril by metal strata.50,51 Curcumin also protects the neurons from oxidative
binding28–30 Thus, altogether it reduces the progression of damage by restoring mitochondrial membrane potential,
neuronal damage in AD brains.31 Studies have confirmed that upregulation of Cu-Zn superoxide dismutase, and inhibiting
the formation of reactive oxygen species is an important the production of intracellular ROS.47 Curcumin also shields
mechanism in AD pathogenesis.28 Curcumin has known to against A53T alpha-synuclein-induced toxicity and GSH dimi-
possess potent antioxidant and free radical scavenging activ- nution in the brain by improving the GSH levels.52 Curcumin
ity32,33. It inhibits lipid peroxidation which in turn reduces not only delays rotenone-induced neuronal loss in human dopa-
amyloid accumulation and oxidative stress-mediated neuro- minergic neuroblastoma cells, but it also inhibits NF-κB trans-
toxicity.28,34,35 Oxidative stress increases the concentration of location, AP-1 activation, and expression of GFAP and iNOS
metals like copper, zinc, or iron in the brain. When the con- proteins. It has also been reported to inhibit the activation of
centrates of these metals reaches more than 1 mM, their affin- astrocytes and microglial cells.53 Altogether, the ability of cur-
ity toward Aβ increases. This results in increase in peptide cumin to protect the dopaminergic neurons by inhibiting the
aggregation and enhanced plague formation, which ultimately decrease of mitochondrial membrane potential (MMP) con-
leads to disease progression.34 Increase in the oxidation of the firms its anti-apoptotic properties.54 Studies using transgenic
proteins have been reported in the AD.36 Isoprostanes (prosta- PD model of Drosophila showed that curcumin reduces the
glandin-like compounds formed in vivo from the free radical- levels of lipid peroxidation and protein carbonyl aggregates in
catalyzed peroxidation of essential fatty acids) levels has been the brains.55
found to increase in the postmortem ventricular CSF of the
subjects with AD. This suggests that brain lipid peroxidation
5.3 | Aging-associated neuro-dysfunctions
can be used as a target to in the management of AD.37 Cur-
cumin extensively decreases the level of oxidized proteins,38 Aging is marked by progressive changes both morphologically
and isoprostanes.36,39 Furthermore, it suppresses GSK-3β- and physiologically in cells, tissues, and organs. The underly-
stimulated Presenilin-1 (PS-1) activity and inhibits further ing mechanisms behind these alterations are still unclear.56
production of Aβ.40 Curcumin because of its free radical scav- Aging not only decreases the functional capacity of vital
enging and protein aggregation inhibition could be a potential organs, but it also increases the vulnerability to diseases.57 It
therapeutic value in AD. has been reported to affect genes which control important func-
tions like biotransformation, bioregulation, free radical scav-
enging activity, DNA repair, cellular cytoskeleton, and
5.2 | Parkinson's disease
apoptosis.58 As the radical scavenging activity is reduced with
Parkinson's disease (PD) is one of the major neurodegenera- aging with a marked increase in ROS levels.59 It is known that
tive diseases characterized by progressive loss of dopaminer- canonical replicative senescence of cells is mainly due to ROS
gic neurons in substantia nigra compacta (SNpc), deposition generation that damages telomeric and nontelomeric DNA.57
of α-synuclein and Lewy bodies.41,42 The cardinal signs of Generally, aging makes a person vulnerable to various neuro-
Parkinson disease include rigidity, tremor, slothfulness of degenerative disorders, cardiovascular diseases, diabetes, arthri-
movement, bradykinesia, impaired gait, and body imbal- tis, and other chronic diseases.58 These results suggest that
ance.43 High levels of free radicals and compromised mito- increase in ROS generation, reduction in radical scavenging
chondrial functions are found to be the main causes of ability, increase in inflammatory proteins, and other oxidative
neuronal death in PD brains.44,45 The neurotoxin 1-methyl- stress responses are the main molecular mechanisms underly-
4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively ing the process of aging. Curcumin has been known to slow
damages mitochondrial complex I of electron transport down the aging process and hence is also used in various cos-
chain, triggering oxidative stress, and thereby producing meceutical preparations60. Curcumin exhibits anti-aging activ-
dopaminergic degeneration.46–48 ity through different molecular pathways and modulating
As reported in several investigations in vitro and various transcription factors like AP-1, SP-1, p53, STAT-3,
in vivo, curcumin possesses antioxidant, anti-inflammatory, ATF3, Nrf2, PPAR-γ, CHOP, HIF-1α, β-catenin, and NF-κB,
anti-apoptotic activities, and therapeutic potential in neurode- and growth factors and their receptors like HER2 and
generative disorders.47,49 Curcumin shields dopaminergic neu- EGFR.56,58 It also mediates its protective mechanisms by bind-
rons against MPTP-induced neuronal damage.45 It also causes ing with the cellular enzymes such as protein kinases (PKA,
increase of dopamine50 and tyrosine hydroxylase (TH), by PKC, FAK, and Src), glutathione S-transferase, DNA
inhibiting the glial fibrillary acidic protein (GFAP) and iNOS topoisomerase-II, telomerase, heme-oxygenase-1, p300 histone
protein expression.51 Using rat models, it has been confirmed acetyltransferase, metalloproteinases, lipoxygenase (5-LOX),
BHAT ET AL. 5

cyclooxygenase-2 (COX-2), chemokines, and interleukins adverse effects make it a drug of choice over other therapeutic
(IL-1, IL-6, and TNF-α). Overall, curcumin's antioxidant options for treating cerebral stroke76,77. Due to its antioxidant
potential is executed mainly by suppressing NF-κB signaling property because of the presence of phenolic and diketonic
pathway58 and by activating transcriptions factors AP-1 and moieties in its chemical structure, curcumin possesses the
Nrf2. It also exerts anti-aging activity by inducing sirtuins and unique anti-ischemic activity78. Curcumin upon oral or intra-
HDAC activation resulting in the reduction of HAT and pro- peritoneal administration lowers lipid peroxidation levels.79,80
motion of neurogenesis.61 Curcumin significantly reduces IL-6, TNF-α in the brain. It is
also reported to reduce protein expression of p53 and Bax sig-
nificantly, whereas Bcl-2 and Sirt1 were increased following
5.4 | Stroke
CUR treatment81. This suggests that curcumin could be used
Stroke is the third major leading cause of death worldwide. as a potential therapeutic agent for the treatment of stroke.
Stroke is clinically defined as interrupted or reduced blood
flow to the brain, which results in functional impairments.62
Cerebral stroke can be categorized into three types:
5.5 | Autism
Autism Spectrum Disorder (ASD) is a multi-syndrome disorder
1. Ischemic (clots or thrombus) stroke occurs due to affecting brain development.82 The major symptoms of ASD
obstruction inside a blood vessel62 include reduced social interest, anxiety, irritable nature, aggres-
2. Hemorrhagic (bleeds) stroke occurs due to leakage or sion, epilepsy, and sensory processing disorder manifested as
rupture of blood vessels63 repetitive and stereotypic behavior.83–85 Stimulation of matrix
3. Transient ischemic attack (TIA) is caused by a tempo- metalloproteinases triggers the neuroinflammatory reactions
rary clot. such as increased secretion of inflammatory cytokines and mito-
chondrial dysfunction that lead to neuronal damage and result
Main symptoms found in stroke are fatigue, vertigo, in the manifestation of autistic phenotype.86 In ASD patients,
impaired gait, loss of balance and coordination, blurred major mutations in cell adhesion molecules such as neurexins
vision, difficulty in swallowing, slurred speech, speech loss, and neuroligins genes have shown a stronger correlation with
numbness or weakness in limbs and facial muscles, head- ASD.87 Activated immune cells and pro-oxidant environmental
ache, and muscle paralysis. toxin generates ROS that results in mitochondrial dysfunction.
Dietary substances like omega-3 fatty acids and flavonoids MMP-9 induces pro-inflammatory response by activating TNF-
have been reported to exert a vast impact on brain health,64–66 α and pro-inflammatory cytokines.
mainly by preventing the diseases related to brain, including In propionic acid-induced ASD rat model, it has been
stroke.67 Dietary components induce genetic as well as epige- reported that curcumin administered (50, 100 and 200 mg/kg)
netic mechanisms that compensate stroke or stroke-like dis- orally significantly decreases the levels of TNF-α and MMP-9
eases.68 Curcumin is known to exert both genetic and in a dose-dependent manner.84 Curcumin also leads to down-
epigenetic influence and can provide vascular protection in regulation of MMP-9 in blood mononuclear cells.88 Anxiety is
patients prone to stroke.69 Curcumin exerts its protective effects also one of the major progressive indications of ASD. Curcumin
mainly through four important mechanisms: Free radical scav- is reported to facilitate the anti-anxiety activity by GABAergic
enging potential and inhibiting the increase in nitric oxide syn- and nitrergic modulation.89 Curcumin can be a desired drug
thesis and lipid peroxidation levels.70,71 molecule which can be used to treat autism, however further
testing is required to evaluate the molecular mechanism.
1. Anti-inflammatory activity by suppressing the produc-
tion of interleukins (IL-1, IL-8, and TNF)72
5.6 | Multiple sclerosis
2. Anti-lipidemic activity by lowering cholesterol and boo-
sting up HDL levels73 Multiple sclerosis is a chronic autoimmune neurodegenerative
3. Curcumin inhibits platelet aggregation factor by interfer- disorder of the nervous system. The basic pathogenesis
ing with the kinase activity of Syk and the subsequent involves the attack of immune system on the myelinated fibers,
activation of PLCgamma2.74 resulting in delay in nerve conduction and permanent damage
to the nerve fibers and neurons. The main symptoms are
Curcumin also inhibits the increase of the GPIIb/GPIIIa fatigue, prolonged double vision or blurred vision, difficulty in
expression of thrombin-activated platelets in a concentration- walking, numbness or tingling sensation in different parts of
dependent manner and prevents adhesion of platelets to brain the body, difficulty in coordination and balance, muscle stiff-
microvascular endothelial cells.75 Curcumin, due to its lipo- ness, and muscle spasms.90 On the basis of potent antioxidant
philic nature, penetrates blood–brain barrier (BBB). Its low and anti-inflammatory properties, curcumin has been thought
6 BHAT ET AL.

to be a potential therapeutic candidate in multiple sclerosis.91 suppresses protein aggregation which delays progression of dis-
Curcumin decreased the penetration of inflammatory cells into ease in ALS mouse model.103 ALS exhibits a complex multi-
spinal cord, and reduced the accumulation of myelin basic pro- factorial in pathogenesis involving unclear interactions
tein (MBP) reactive lymphocytes, and down-regulated the between genetic susceptibility and environmental risk factors.
expression of TGF-β, IL-6 IL-17, IL-21, RAR-related orphan Strong evidence support the involvement of oxidative stress
receptor gamma (RORγt), and STAT3 in an experimental rat in ALS pathogenesis. Although attempts in humans to delay
model of autoimmune encephalomyelitis (EAE).91 Curcumin the clinical progression of the disease with antioxidants have
protects the mitochondria and suppresses the apoptosis by given negative results, a number of clinical trials with antioxi-
inhibiting the mitochondrial and endoplasmic reticulum stress, dants and inducers of cytoprotective enzymes are still in pro-
which results in decreased expression of Caspase 12 and Cyto- gress. Curcumin has been demonstrated to exert its protective
chrome C. Furthermore, the anti-oxidative potential of cur- effects by acting either as a direct (free radical scavenger) or
cumin significantly decreases the neuronal death.92 Activation an indirect (cytoprotective) antioxidant, and therefore, may
of astrocytes promotes neuroinflammation and progression of be considered as a good therapeutic candidate for further stud-
multiple sclerosis. Curcumin suppresses astrocyte activation by ies in ALS patients.8
inhibiting the anti-inflammatory mediators like prostaglandin
E2 (PGE2), NO, and proinflammatory cytokines such as IL-6,
5.9 | Anxiety and depression
IL-1β, and TNF-α. Curcumin also diminished the expressions
of iNOS and COX-2 and inhibited NF-κB pathway.93 Axonal Curcumin has shown to possess a strong antidepressant activ-
degeneration, characteristic pathogenic feature in multiple scle- ity in animal models of depression.104–107 It acts by inhibiting
rosis, is mainly induced by excessive production of nitric the expression of MAO-A and MAO-B enzymes which
oxide, activation of MyD88/p38 MAPK signaling, and JNK results in increase the levels of norepinephrine, serotonin, and
phosphorylation. Tegenge et al.94 showed that curcumin pro- dopamine.108 Curcumin's antidepressant activity is produced
tects the neuronal axons by inhibiting the production of NO by ERK regulated increase in the expression of brain-derived
and JNK phosphorylation. Curcumin seems to be a promising neurotrophic factor (BDNF) expression in the amygdala of
therapeutic candidate for MS. mice.109 Interestingly, curcumin was shown to promote hip-
pocampal neurogenesis and improve BDNF level in mouse
model of chronic stress.110 Curcumin has been reported to
5.7 | Huntington's disease
exert anxiolytic-like effects which were suggested due to the
Huntington's disease (HD) is an autosomal dominant neuro- decreased levels of pro-inflammatory mediators, iNOS and
degenerative disorder caused by abnormally increased intra- COX-2 mRNA via NF-κB signaling pathway.111 Inhibition of
cellular accumulation of the Huntingtin (Htt) protein due to proinflammatory cytokines IL-1β via (NF)-κB pathway con-
repetition polyglutamine (polyQ) repeats95,96 which in turn firms its anti-inflammatory activity in depression.112
produces inclusion bodies (IBs) and leading to the develop-
ment of motor disabilities in HD patients. Common symp-
5.10 | Glioma
toms include involuntary movements, abnormalities in gait,
posture, and balance, obsessive–compulsive behavior, and Curcumin suppresses malignant gliomas by modulating cel-
memory loss.97 Subcellular actions like oxidative stress, lular proliferation,113 apoptosis (decreases in bcl-2, bcl-xL,
mitochondrial dysfunction, inflammation, and transcriptional and caspases activation),114 autophagy,115 angiogenesis,116
dysregulation play a major role in the progression of HD.98 immunomodulation,117 invasion,118 and metastasis.119 It is
Curcumin, because of its ability to cross the BBB,99 has reported to selectively kill the tumor cells without affecting
been investigated for its therapeutic effects against various the normal neural cells like astrocytes and neurons.115 It can
motor neurodegenerative disorders. Curcumin has been also induce autophagy, which is regulated by simultaneous
shown to reverse the polyQ-induced apoptosis and neuronal inhibition of Akt/mTOR/p70S6K pathway and stimulation
dysfunction in motor areas of HD patients.100,101 Thus, cur- of ERK1/2 pathway.120 Put together, these studies suggest
cumin is seen as potential therapeutic candidate in polyQ the anti-tumor potential of curcumin. However, detailed
disease patients.98 research in vitro and preclinical models is required before
the clinical trials.
5.8 | Amyotrophic lateral sclerosis
5.11 | Prion diseases
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative dis-
ease, characterized by progressive loss of the upper and lower Prion diseases, also known as transmissible spongiform
motor neurons at the spinal or bulbar level.102 Curcumin encephalopathies, are invariably fatal neurodegenerative
BHAT ET AL. 7

diseases for which there are no efficacious treatments.121 neurodegenerative diseases by altering the expression of NF-
Prions are transmitted to tissue and induce abnormal folding κB cascade.131,133,134 PPAR-γ is highly expressed in hippo-
of some specific proteins and transform them into patho- campal region of the brain.135 PPAR-γ directly or indirectly
genic agents called prion proteins (PrP).122 As PrP are insol- influences the expression of genes (TFAM, NRF1, NRF2,
uble or not metabolized by cellular enzymes, they Bax, and Bcl-2) that are involved in neurodegeneration.
accumulate and slowly aggregate to form plagues. It disrupts Activation of NF-κB pathway triggers inflammation by
neuronal morphology and its functions. Aggregation of mediating the release of proinflammatory factors like IL-1,
prion plaques leads to memory loss, personality change, and IL-6, MAP-1, CCL5, COX-2, iNOS, MMP-9, and
movement disorder. TNF.136,137 This inflammation leads to progressive loss of
Curcumin binds and inhibits the aggregation of PrP in the neuronal matter and results in the aggravation of neuro-
scrapie-infected neuroblastoma (scNB) cells.123 It has been logical diseases like stroke, AD, PD, HD, and MS.136 Cur-
reported to revert molecular chaperone (heat shock proteins) cumin has been reported to up-regulate PPAR-γ. This has
dysfunction, which is necessary for protein refolding and been reported to suppress the inflammatory NF-κB path-
degradation of misfolded aggregates from the cell.124 It can way.138 Curcumin activates PPAR-γ which reduces the
efficiently rescue the neuronal cells from amyloid-induced β-amyloid stimulated inflammatory response in astrocytes
apoptosis and oxidative stress.125 These results confirm the thus inhibits the progression of AD.139 Curcumin also pre-
significant therapeutic potential of curcumin in Prion vents the progressive loss of dopaminergic neurons in SNpc
diseases.
by inhibiting the inflammation triggered by NF-κB pathway
via PPAR-γ pathway.140
5.12 | Spinal muscular atrophy
Spinal muscular atrophy (SMA) is a fatal autosomal reces- 7 | PHARMACOKINETICS/
sive pediatric neurodegenerative disease characterized by BIOAVAILABILITY OF CURCUMIN:
destruction of motor neurons, resulting in atrophy of skeletal PROBLEMS AND PROMISES
muscles and generalized weakness. It is caused by homozy-
gous disruption of the survival motor neuron 1 (SMN1) gene The absorption, distribution, metabolism, and excretion of cur-
either by deletion, conversion, or mutation. There are no cumin in rodents have been reported by several studies.141–143
medical treatments for SMA except for the anti-sense oligo- Following oral administration, curcumin exhibits poor absorp-
nucleotide SPINRAZA® (nusinersen).126,127 Several investi- tion and undergoes fast biotransformation, which results in
gations have elucidated possible mechanisms underlying the reduced systemic bioavailability, and only traces of the com-
molecular pathogenesis of the disease128 proposing the role pound enter the systemic circulation. Maximum amount of it is
of the oxidative stress in the progression of SMA. Curcumin excreted in the feces. Limited penetration in the brain and testis
is considered as one of the choices in the treatment of SMA, are reported.144,145 The BBB is formed of endothelial cells
not only because of its strong antioxidant and anti- which restricts the entry of substances into the brain and acts as
inflammatory activity but also because it promotes SMN a protective shield. Highly lipid soluble and low molecular
activity and induces the production of full-length SMN weight drug substances have been reported to cross the BBB
protein.129 and enter into the brain. A number of studies have been carried
out to determine the distribution of curcumin and its formula-
6 | PPAR γ A S A TH E R A P E U T I C tion in brain. Tsai et al.77 compared the distribution of conven-
TARGET IN NEURODEGENERATIVE tional curcumin and poly(lactic-co-glycolic acid) (PLGA)
DISEASES AND THE ROLE OF nanoparticles encapsulated curcumin in brain. They reported
CURCUMIN that nanoformulation of curcumin concentrated more in cere-
bral cortex and hippocampus with better retention time
Peroxisome proliferator-activated receptor gamma (PPAR-γ) (Table 1).
is a ligand-activated transcriptional factor that belongs to the Analytical determination of curcumin nanoformulation
nuclear hormone receptor superfamily. PPAR-γ influences reveals that curcumin is distributed in liver, heart, spleen,
the activity of several intracellular second messengers and lung, kidney, and brain. Nanoformulations are found to
their signaling cascade, including regulation of insulin sensi- increase AUC, t1/2, and mean residence time of curcumin in
tivity, glucose homeostasis, fatty acid oxidation, immune all these organs, except the heart.77 These results provide
responses, redox balance, cardiovascular integrity, and cell information and research leads to the effectiveness and limi-
fate.130–132 Recent studies have reported that activation of tation of curcumin usage as therapeutics against different
PPAR-γ reduces the development and progression of diseases (Table 2).
8 BHAT ET AL.

T A B L E 1 Pharmacokinetic profile of curcumin and C-NPs in of curcumin which have higher solubility profile and slower
different brain regions following intravenous administration biotransformation rate and hence enhance its bioavailability.
AUC MRT Some of the nanoformulations of curcumin are discussed
Brain regions t1/2 (min) (min μg/mL) (min) below:
Cerebral cortex C 2.32 ± 0.04 5.39 ± 0.78 17.9 ± 0.50
C-NPs 19.9 ± 2.63 6.55 ± 2.33 35.1 ± 4.50 7.1.1 | Phospholipid complexes
Cerebellum C 16.9 ± 0.79 2.09 ± 0.24 31.5 ± 1.62
Many studies have shown that complexation of curcumin
C-NPs 17.9 ± 3.17 5.01 ± 2.24 30.6 ± 5.11 with different phospholipids enhances the bioavailability of
Hippocampus C 7.56 ± 0.87 10.8 ± 1.42 16.5 ± 0.39 curcumin. Phospholipids are lipophilic substances which
C-NPs 16.7 ± 2.56 11.7 ± 4.50 30.2 ± 4.25 form the basic structure of the cellular membrane. They are
Brain stem C 12.4 ± 0.79 2.49 ± 0.28 22.5 ± 1.10 miscible in both hydrophilic and lipophilic environments
C-NPs 10.7 ± 1.55 3.96 ± 1.43 24.5 ± 2.09
and have the ability to act as a carrier for the drug thereby
facilitating its movement across the biological membrane.
Striatum C 13.0 ± 1.98 1.74 ± 0.35 24.1 ± 1.35
Curcumin complexed in a phospholipid has been reported to
C-NPs 11.7 ± 0.66 3.01 ± 1.24 23.3 ± 1.06
have better bioavailability (125.80%) as compared to con-
The rest brain C 12.1 ± 1.10 2.81 ± 0.89 21.9 ± 1.22 ventional curcumin.146 Encapsulating curcumin in polyvinyl
C-NPs 11.0 ± 1.94 5.54 ± 3.57 22.4 ± 2.92 caprolactam–polyvinyl acetate polyethylene glycol graft
Abbreviations: C, curcumin; C-NPs, curcumin PLGA nanoparticles; AUC, area copolymer solidified powder has been shown to change the
under the concentration–time curve; MRT, mean residence time; t1/2, half-life. state of curcumin from crystalline to amorphous form, due
to which its bioavailability improves significantly.147

T A B L E 2 Pharmacokinetic profile of curcumin and C-NPs in rat

organs following intravenous administration 7.1.2 | Emulsion-based delivery systems
AUC MRT Microemulsions, self-microemulsion, and nanoemulsion are
Organs t1/2 (min) (min g/mL) (min) reported to enhance the bioavailability of drugs that are poorly
Liver C 17.6 ± 2.20 9.06 ± 1.55 33.0 ± 1.94 water-soluble.148 These emulsions of curcumin have been
Heart C-NPs 19.8 ± 1.50 71.3 ± 11.7 35.4 ± 2.40 found to increase the oral bioavailability of curcumin. Numer-
C 37.5 ± 9.31 3.03 ± 0.85 57.0 ± 11.1 ous studies have reported on the emulsion-based delivery sys-
tems for curcumin.149–152 Bergonzi et al.153 found that a
C-NPs 13.4 ± 1.81 2.82 ± 1.14 27.1 ± 2.80
curcumin microemulsion formulation made up of food grade
Spleen C 12.6 ± 2.46 5.72 ± 1.14 25.6 ± 2.65
components increased its oral absorption by 70%. In addition,
C-NPs 14.2 ± 0.96 1,213 ± 102 28.1 ± 1.18
a self-microemulsion formulation of curcumin has been
Lung C 13.2 ± 1.16 8.98 ± 1.82 26.1 ± 1.11 proven to increase the absorption of curcumin by 3.86 times
C-NPs 15.1 ± 0.48 196 ± 23.1 30.6 ± 0.36 as compared to conventional curcumin suspension when
Kidney C 19.7 ± 1.13 12.0 ± 0.88 35.4 ± 1.38 administered orally.154 In 2012, Yu and Huang developed an
C-NPs 48.8 ± 0.81 16.0 ± 1.78 75.7 ± 1.22 organol-gel based nanoemulsion formulation of curcumin
Brain C 9.20 ± 1.84 4.04 ± 0.22 20.4 ± 0.95 which also shows better bioavailability.155
C-NPs 14.8 ± 1.31 5.68 ± 1.44 27.1 ± 2.04

Pharmacokinetic parameters of curcumin and C-NPs in rat organs following i.v.

7.1.3 | Liposomes
administration.
Liposomes are defined as a phospholipid bilayer encapsulating
Abbreviations: C, curcumin; C-NPs, curcumin PLGA nanoparticles; AUC, area
under the concentration–time curve; MRT, mean residence time; t1/2, half-life. an aqueous core. They have been used to enhance the oral
bioavailability of hydrophobic drugs. Several studies have
confirmed that encapsulating curcumin in liposomes enhances
its hydrophilicity by ninefold compared to unformulated
7.1 | Strategies to enhance bioavailability of curcumin.155–157 Furthermore, curcumin entrapped within lipo-
curcumin
somes coated with chitosan shows better pharmacokinetic profile.
Curcumin has a wide range of therapeutic activity, however, it Here, the encapsulation efficacy was reported to be 97.40%.157
has not been exploited because of its poor bioavailability. Vari- Reports also indicate that co-administration of lecithins improves
ous strategies have been employed to increase its bioavailabil- the bioavailability of curcumin. Takahashi et al.158 made a
ity. Nanotechnology has been used to prepare nanoformulations new formulation of curcumin encapsulated in lecithin-coated
BHAT ET AL. 9

liposomes and reported good dispersion and increased the plasma pigs, rats and monkeys did not produce any toxic effects.165
levels in Sprague–Dawley rats. The reported acute LD50 of curcumin oil in rats exceeds
5 g/kg.166 Dadhaniya et al.167 performed acute and sub-
chronic toxicity studies of curcumin in rats and mice. The
7.1.4 | Polymeric micelles
oral LD50 value in both rats and mice was reported to be
Polymeric micelles generally form micelles with a size rang- higher than 2,000 mg/kg bw/day.
ing between 20 and 100 nm in aqueous solution. This is
because of the presence of amphiphilic block copolymer in
its structure.159 These polymeric micelles have been exten- 8.2 | Short-term study
sively used for the solubilization of hydrophobic drugs.
Rats and monkeys fed with 1.8 g/kg and 0.8 mg/kg of curcumin
Polymeric micelles of curcumin have shown 162-fold higher
respectively, for a period of 3 months showed no signs of toxic-
biological half-life and have been shown to increase the vol-
ity.164,168 Consumption of 5% ethanolic extract is reported to
ume of distribution by 70-fold in comparison to the conven-
produce hepatotoxicity in mice and rats.169 Mice fed with tur-
tional curcumin.160 Schiborr et al.161 found that liquid
meric extracts (0.05 or 0.25%) for 14 days are reported to show
curcumin micelles increase the mean plasma Cmax of cur-
coagulative necrosis in the liver accompanied by a zone of reg-
cumin versus curcumin given in the powdered form.
enerating hepatic parenchymal cells on histopathological exami-
nation. It was reported that mice appear to be a susceptible
7.1.5 | Curcumin nanoparticle species for turmeric induced toxicity when compared with rat.170
Nanoparticle formulations have been reported to improve the Doses used in these studies are 200–5,000 times higher than the
solubility of hydrophobic drugs and bioavailability of the drugs. actual daily intake in human. Hence, this is not alarming.
Nanoparticles, when used as drug carriers, are small vesicles
and are reported to have high stability, high carrier capacity and
can be administered by various routes.162 They are mainly clas- 8.3 | Genotoxicity and mutagenicity studies
sified as polymer nanoparticles and lipid nanoparticles. Cui Curcumin has been reported to possess both pro-mutagenic and
et al.154 developed solid lipid-based nanoparticles of curcumin anti-mutagenic effects. In chromosomal aberration assay, cur-
that showed improved pharmacokinetic properties. The relative cumin (100 and 200 mg/kg) was shown to decrease the incidence
bioavailability of solid lipid-based nanoparticles of curcumin of aberrant cells count.171 It is also shown to prevent the mutative
was estimated to be 92.53% as compared to curcumin suspen- effects of urethane, a powerful mutagen.172 Furthermore, cur-
sion. It was also reported that solid lipid-based nanoparticles of cumin was reported to protect against hexavalent chromium-
curcumin disperse in the brain as compared to suspension. Sha- potentiated DNA damage, while chromium and curcumin in
ikh et al.163 developed encapsulated curcumin PLGA combination lead to DNA breaks in human lymphocytes and gas-
nanoparticles and investigated its oral bioavailability in compar- tric mucosal cells.173 On the contrary, curcumin and turmeric are
ison to crude curcumin suspension and a combination of cur- also shown to enhance gamma-radiation-induced chromosome
cumin with piperine (a stabilizing agent, which inhibits the aberration in the Chinese hamster ovarian cells.174
hydrolysis of curcumin). They also reported that the in vivo
pharmacokinetic properties of PLGA nanoparticles of curcumin
show ninefold increase in oral bioavailability when compared 8.4 | Reproductive study
with crude curcumin suspension and a combination of curcumin
with piperine. These investigations are a step toward the estab- In a two-generation toxicity study, male and female rats fed
lishment of curcumin as a therapeutic drug with improved phar- with curcumin (1,500, 3,000–10,000 ppm), showed no
macokinetic and pharmacodynamic profile. adverse or toxic sign at male or female specific toxicity in
parental or in offspring. However, there was a slight decrease
in body weight in parental while as increase body weight was
8 | T O X I C O L O G Y S T U D I E S ON found in F2 pups at the highest tested dose. Thus, the no
CURCUMIN observed adverse effect level (NOAEL) of curcumin in the
two-generation toxicity study was found to be 10,000 ppm.
8.1 | Acute toxicity profile of curcumin Based on this study, the joint FAO/WHO Expert Committee
A single-dose oral administration of 5 g curcumin/kg body on Food Additives (JECFA) recommended the actual daily
weight (bw) in rats is reported to be a nontoxic dose.164 In intake for curcumin as 0–3 mg/kg body weight based on the
addition, oral toxicity studies using 2.5 g turmeric/kg bw or intake of 250–320 mg/kg body weight, in the mid-dose
300 mg/kg bw of an alcohol extracts of turmeric in guinea group.
 10

TABLE 3 Clinical trials on Curcumin for different neurodegenerative diseases (www.clinicaltrials.gov/as on writing date)

S.No. NCT Number Title Conditions Interventions Location

1. NCT03085680 Curcumin and Function in Older Adult • Older Adults • Drug: Curcumin • University of Florida,
• Physical Function • Drug: Microcrystalline cellulose Gainesville, Florida, United
• Cognitive Function States
2. NCT02298985 Curcumin Addition to Antipsychotic • Chronic Schizophrenia • Drug: Curcumin • Beersheva Mental Health
Treatment in Chronic Schizophrenia • Drug: Placebo Center, Beersheva, Israel
Patients • Tirat Carmel Mental Health
Center, Tirat Carmel, Israel
3. NCT013831 18-Month Study of Curcumin • Age-associated Cognitive Impairment • Drug: Curcumin • UCLA Longevity Center, Los
• Mild Cognitive Impairment (MCI) • Other: Placebo Angeles, California, United
States
4. NCT01875822 Open-label Study of Curcumin C-3 • Schizophrenia • Dietary Supplement: • Dr. Michel Woodbury-
Complex in Schizophrenia • Schizoaffective Disorder Super-Curcumin Farina, San Juan, Puerto Rico
• Depression
5. NCT02104752 Curcumin as a Novel Treatment to • Schizophrenia • Drug: Curcumin • VA Greater Los Angeles, Los
Improve Cognitive Dysfunction in • Cognition • Drug: Placebo Angeles, California, United
Schizophrenia • Psychosis States
6. NCT02476708 A Pilot Trial of Curcumin Effects on • Schizoaffective Disorder • Supplement: Curcumin • Health Center, New Haven,
Cognition in Schizophrenia 1,800 mg Connecticut United States
7. NCT01928043 Adjunctive Curcumin for Symptomatic • Bipolar Disorder • Drug: Curcumin • Sunnybrook Health Sciences
Adolescents With Bipolar Disorder: Centre, Toronto, Ontario,
Brain and Body Considerations Canada
8. NCT02532023 The Combined Effects of omega3 Fatty • Migraine • Dietary Supplement: Omega 3 • Tehran University of Medical
Acids and Curcumin Supplementation fatty acid Sciences
on Inflammatory and Endothelial • Dietary Supplement: Curcumin
Factors in Migraine Patients • Dietary Supplement: Omega 3
fatty acid placebo
• Dietary Supplement: Curcumin
placebo
9. NCT00164749 A Pilot Study of Curcumin and Ginkgo • Alzheimer's Disease • Drug: Placebo and ginkgo • The Chinese University of
for Treating Alzheimer's Disease extract Hong Kong, Shatin,
• Drug: Curcumin and ginkgo Hong Kong
extract
10. NCT032238 Curcumin and Vascular and Cognitive • Chronic Kidney Diseases • Drug: Curcumin • University of Colorado at
Function in Patients With Chronic • Cognitive Decline • Other: Placebo Denver, Aurora, Colorado,
Kidney Disease United States
(Continues)
BHAT ET AL.
TABLE 3 (Continued)

S.No. NCT Number Title Conditions Interventions Location

BHAT ET AL.

11. NCT01383161 18-Month Study of Memory Effects of • Age-associated Cognitive Impairment • Drug: Curcumin • UCLA Longevity Center, Los
Curcumin • Mild Cognitive Impairment (MCI) • Other: Placebo Angeles, California, United
States
12. NCT01001637 Efficacy and Safety of Curcumin • Alzheimer Disease • Dietary Supplement: Curcumin • Jaslok Hospital and Research
Formulation in Alzheimer's Disease Formulation Center, Mumbai,
• Dietary Supplement: Placebo Maharashtra, India
13. NCT01811381 Curcumin and Yoga Therapy for those at • Mild Cognitive • Drug: Curcumin • VA Greater Los Angeles
Risk for Alzheimer's Disease • Impairment • Behavioral: Aerobic Healthcare
• Yoga • System, West
• Los Angeles, CA, West Los
Angeles,
• California, United States
14. NCT01750359 Efficacy and Safety Curcumin in • Major Depression • Drug: Curcumin • Tirat Carmel Mental Health
Depression Center, Tirat Carmel, Israel
15. Early Intervention in Mild Cognitive • Mild Cognitive Impairment • Dietary Supplement: Curcumin • Louisiana State University
NCT00595582 Impairment (MCI) With Curcumin + + bioperine Health Sciences Center,
Bioperine Shreveport, Louisiana, United
States
16. Dietary Supplement of Curcumin in • Multiple • Drug: IFN beta-1a • Investigational Site, Naples,
Subjects With Active Relapsing • Sclerosis • + curcumin (BCM 95) Italy
NCT01514370 Multiple Sclerosis Treated With • Drug: IFN beta-1a + placebo
Subcutaneous interferon Beta 1a
17. NCT03150966 The Immunomodulatory Effects of Oral • Multiple Sclerosis • Drug: Nanocurcumin • Drug Applied Research
Nanocurcumin in Multiple Sclerosis • Drug: Placebo Center, Tabriz, Iran, Tabriz,
Patients Iran, Islamic Republic of
18. NCT00099710 Curcumin in Patients With Mild to • Alzheimer's Disease • Dietary Supplement: Curcumin • UCLA Medical Center,
Moderate Alzheimer's C3 Complex Westwood, California, United
Disease States
19. NCT01712542 Curcumin Bioavailability in Glioblastoma • Glioblastoma • Curcumin • •Department of
Patients Neurosurgery, Johann
Wolfgang Goethe-University,
Frankfurt, Hessen, Germany
20. NCT01022632 Effect of Curcumin as Nutraceutical in • Major Depressive Disorder • Dietary Supplement: Curcumin • Sir Takthasinhji General
Patients of depression • Drug: Fluoxetine Hospital, Bhavnagar, Gujarat,
• Dietary Supplement: Curcumin India
and Fluoxetine
(Continues)
11
12 BHAT ET AL.

8.5 | Neurotoxicity

• Edinburgh, United Kingdom

Center, Boulder, Colorado,
Several animal and clinical trials confirm that curcumin pos-

London, United Kingdom

• University of Colorado sesses neuroprotective activity.9,175,176 Based on literature
Translational Research
survey, we could not find any report that confirmed or
Boulder, Clinical

claimed the neurotoxic effect of curcumin.

United States
Location

9 | SIDE EFFECTS OF CURCUMIN

Curcumin has been recognized to be safe by USFDA with

no toxic effects. However, some studies reported that cur-
• Drug: High-dose curcumin pill
• Drug: Low-dose curcumin pill

cumin induces dose-dependent chromosomal aberrations

and DNA alterations in several mammalian cell lines at a
concentration of 10 mg mL−1.177,178 A study carried by
National Toxicology Program (USA)179 reported extensively
• Drug: Placebo pill

carcinogenic effects of oleoresin, an organic turmeric extract

Interventions

which is used in food items as an additive. Oleoresin con-

• Curcumin

tains 79–85% of curcumin similar to that of commercial

grade curcumin. Mice were given oleoresin at different con-
centrations in diet for about 2 years to find the possible car-
cinogenic and toxicity effects. Gastric ulceration,
hyperplasia, and inflammation of stomach, colon, and cecum
were observed in rodents.179 In mice, augmented frequency
of thyroid gland follicular cell hyperplasia was also reported.
Increase in the frequencies of clitoral gland adenomas, hepa-
tocellular adenomas, carcinomas of the small intestine, and
• Alzheimer's Disease

hepatocellular adenomas was reported in rodents at a daily

• Plaque, Amyloid
• Vascular Aging

dose of curcumin 0.2 mg kg−1 body weight.9 It has been

reported that curcumin promotes lung cancer in mice.180
Conditions

Curcumin affects the metabolism of various drugs by

inhibiting cytochrome P450, glutathione-S-transferase, and
UDP-glucuronosyl transferase,181 thereby leading to an
increase in plasma concentration of drugs and toxicity.182 To
the best of our knowledge, as of today (May 12, 2019), there
Cognitive Health in Ageing Register:

are no reports on long term toxicity information on curcumin

Prospective Readiness Cohort Study
Oral Curcumin Supplementation in

Adults Improve Vascular Function

Observational and Trial Studies in

in humans.
Middle-Aged and Older

10 | CLINICAL TRIALS ON
Dementia Research:

CURCUMIN FOR
Investigational

NEURODEGENERATIVE DISEASES

Clinical trials conducted so far on curcumin have confirmed

Title

its therapeutic potential in the treatment of various neurode-

generative diseases.183 A search on www.clinicaltrials.gov
(accessed in April 2019) indicated around 15 ongoing clini-
(Continued)

NCT01968564

NCT02114372
NCT Number

cal trials on curcumin to ascertain the efficacy of curcumin

in the treatment of different neurological diseases. Although
clinical trials on curcumin are being carried out throughout
the world, substantial proportion of them being conducted in
TABLE 3

the USA. A team from the University of California, Los

S.No.

Angeles has started a trial to confirm whether curcumin is

21.

22.

effective in the management of Schizophrenia.184 Similarly,

BHAT ET AL. 13

TABLE 4 Patents on Curcumin in India (http://ipindiaservices.gov.in/PublicSearch/PublicationSearch/Search)

S no. Patent no. Title Date

1 201741040570 A method of identifying isomers of curcumin and preferential November 14, 2017
stabilization of one of them
2 201747033291 Anti-age composition comprising a combination of antioxidant September 20, 2017
agents in association with bifidobacteria and cell walls isolated
from probiotics
3 201741023245 A topical wound healing formulation for faster and beneficial July 2, 2017
antimicrobial and wound healing effect
4 201747016921 Human therapeutic agents May 15, 2017
5 201727008890 Composition for reducing local fat and body weight and March 15, 2017
pharmaceuticals and use thereof
6 201731001972 Hybrid cotton patch and a method for its fabrication January 18, 2017
7 201627042204 Curcumin peptide conjugates and formulations thereof December 9, 2016
8 201647036593 Curcumin compositions and uses thereof October 25, 2016
9 201741040570 A method of identifying isomers of curcumin and preferential November 14, 2017
stabilization of one of them
10 201617027974 Compositions containing extracts of Curcuma longa and August 17, 2016
Echinacea angustifolia which are useful to reduce peripheral
inflammation and pain
11 201617019785 Modified release therapeutic systems for oral administration of June 9, 2016
curcumin in the treatment of intestinal disorders
12 201641012389 Methods and compositions to treat sexually transmitted infections April 7, 2016
(stis) and sexually transmitted infections mediated inflammation
13 201631006546 “Microwave-mediated processing of turmeric” February 25, 2016
14 201641006388 A composition comprising Salvia officinalis February 24, 2016
15 201641006389 A composition comprising ursolic acid, and February 24, 2016
16 201641006391 A composition comprising ethylhexylglycerin February 24, 2016
17 201631005351 Slowly digestible starch–casein nanoparticles for colon targeted February 16, 2016
controlled delivery of biologically active agents in foods
18 201621000367 Anti-inflammatory and pain-relieving formulation to support January 5, 2016
overall joint health
19 6813/CHE/2015 Metformin–curcumin hybrid drug conjugate for enhanced December 21, 2015
anticancer potential
20 6203/CHE/2015 Novel herbal combinations for the treatment of inflammatory November 18, 2015
diseases
21 4269/MUM/2015 Curcumin compositions for improvement in cardiovascular flow November 9, 2015
22 5721/CHE/2015 Turmeric mouth rinsing in the treatment of gingivitis October 26, 2015
23 9621/DELNP/2015 Regulation of cancer using natural compounds and/or diet October 14, 2015
24 4543/CHE/2015 Fibrin wafer for sustained local delivery of human albuminated August 28, 2015
curcumin
25 201617027974 Compositions containing extracts of Curcuma longa and August 17, 2016
Echinacea angustifolia which are useful to reduce peripheral
inflammation and pain
26 201617019785 Modified release therapeutic systems for oral administration of June 9, 2016
curcumin in the treatment of intestinal disorders
27 201641012389 Methods and compositions to treat sexually transmitted infections April 7, 2016
(stis) and sexually transmitted infections mediated inflammation
28 201631006546 “Microwave-mediated processing of turmeric” February 25, 2016
(Continues)
14 BHAT ET AL.

TABLE 4 (Continued)

S no. Patent no. Title Date

29 201641006388 A composition comprising salvia officinalis February 24, 2016
30 201641006389 A composition comprising ursolic acid February 24, 2016
31 201641006391 A composition comprising ethylhexylglycerin February 24, 2016
32 201631005351 Slowly digestible starch–casein nanoparticles for colon targeted February 16, 2016
controlled delivery of biologically active agents in foods
33 201621000367 Anti-inflammatory and pain-relieving formulation to support January 5, 2016
overall joint health
34 6813/CHE/2015 Metformin–curcumin hybrid drug conjugate for enhanced December 21, 2015
anticancer potential
35 6203/CHE/2015 Novel herbal combinations for the treatment of inflammatory November 18, 2015
diseases
36 4269/MUM/2015 Curcumin compositions for improvement in cardiovascular flow November 9, 2015
37 5721/CHE/2015 Turmeric mouth rinsing in the treatment of gingivitis October 26, 2015
38 9621/DELNP/2015 Regulation of cancer using natural compounds and/or diet October 14, 2015
39 4543/CHE/2015 Fibrin wafer for sustained local delivery of human albuminated August 28, 2015
curcumin
40 4444/CHE/2015 A novel formulation for anti-inflammation containing curcumin August 25, 2015
and ginger
41 4442/CHE/2015 A novel formulation for anti-inflammation containing hyaluronic August 25, 2015
acid
42 3205/MUM/2015 Herbal-based anti-fungal topical formulation for subcutaneous August 21, 2015
infection
43 2574/MUM/2015 Compositions containing nanosize phospholipid–curcumin July 6, 2015
complex and process of preparation thereof
44 2530/MUM/2015 A nutraceutical formulation and a process for production thereof July 2, 2015
45 2531/MUM/2015 A nutraceutical formulation and a process for production thereof July 2, 2015
46 2529/MUM/2015 A nutraceutical formulation and a process for production thereof July 2, 2015
47 3290/CHE/2015 Cocrystal of trigonelline June 29, 2015
48 1904/KOLNP/2015 Curcumin solubilizate June 17, 2015
49 630/KOL/2015 Curcumin infused milk beverage and a process for the preparation April 06, 2015
thereof
50 1112/DEL/2015 A novel bioconjugate drug for targeted treatment of cancer and April 22, 2015
cancer stem cells
51 1942/DELNP/2015 Methods and compositions useful for improving bone and joint March 10, 2015
health
52 497/DEL/2015 A new herbal formulation as preventive major for various cancer February 21, 2015
and neurological diseases treatment
53 97/DEL/2015 An improved process for the preparation of curcuminods from January 13, 2015
turmeric (Curcuma longa L.) Oleoresin
54 2552/MUMNP/2014 Improved complexes and compositions containing curcumin December 16, 2014
55 6309/CHE/2014 A process for preparation of bioavailable white curcumin—A December 15, 2014
unique blend of hydrogenated curcuminoids
56 3011/DEL/2014 Oral dosage form for sustained release of curcumin October 21, 2014
57 2860/DEL/2014 Dermal patch of curcumin for therapeutic uses October 8, 2014
58 4931/CHE/2014 Novel solid state forms of curcumin September 30, 2014
59 4538/CHE/2014 Method of manufacturing oil based natural colors for cosmetic and September 18, 2014
pharmaceutical importance using solid lipid liposomal
microencapsulation technology
(Continues)
BHAT ET AL. 15

TABLE 4 (Continued)

S no. Patent no. Title Date

60 4338/CHE/2014 Succinyl chitosan-fish collagen-poly ethylene glycol (peg) based September 4, 2014
composite hydrogel system containing microencapsulated
curcumin for subcutaneous wound healing
61 4256/CHE/2014 Poly(glycerol sebacate) based materials for food packaging September 1, 2014
applications
62 2428/DEL/2014 Process for making low residual solvent curcumin August 26, 2014
63 4145/CHE/2014 A herbal formulation for the enhancement of male sexual function August 25, 2014
64 2497/MUM/2014 “Novel 1,2,4-triazoloquinazolines derivatives of curcumin and August 4, 2014
process for preparation thereof”
65 2496/MUM/2014 “Novel coumarin derivatives of curcumin and process for August 4, 2014
preparation thereof”
66 201631006546 “Microwave-mediated processing of turmeric” February 25, 2016
67 201641006388 A composition comprising salvia officinalis February 24, 2016
68 201641006389 A composition comprising ursolic acid, and February 24, 2016
69 201641006391 A composition comprising ethylhexylglycerin February 24, 2016
70 201631005351 Slowly digestible starch–casein nanoparticles for colon targeted February 16, 2016
controlled delivery of biologically active agents in foods
71 201621000367 Anti-inflammatory and pain-relieving formulation to support January 5, 2016
overall joint health
72 6813/CHE/2015 Metformin-curcumin hybrid drug conjugate for enhanced December 21, 2015
anticancer potential
73 6203/CHE/2015 Novel herbal combinations for the treatment of inflammatory November 18, 2015
diseases
74 2508/MUM/2013 Colon targeted pharmaceutical composition of esomeprazole July 29, 2013
magnesium trihydrate and curcumin
75 2509/MUM/2013 “Multiparticulate pharmaceutical composition of etodolac and July 29, 2013
curcumin”
76 3161/CHE/2013 “A composition to enhance immunity and growth for children” July 15, 2013
77 1733/DEL/2013 Curcumin conjugated gd nanoparticles for imaging and therapy. June 11, 2013
78 1785/MUM/2013 (1) Curcumin enriched flavored skim milk health beverage; (2) May 20, 2013
production technology of curcumin enriched flavored skim milk
health beverage; (3) clinical assessment of skim milk health
beverage for therapeutic efficacy
79 2200/CHE/2013 Development of soluble albuminated curcumin for application in May 20, 2013
cancer therapy
80 1516/CHE/2013 Fibrin wafer/disc as a biological carrier for sustained delivery of May 3, 2013
curcumin
81 413/KOL/2013 A pharmaceutical combination for treating tuberculosis April 15, 2013
82 879/DEL/2013 Multi-functional natural healing matrix wound bed for wound March 22, 2013
healing bandage/dressing
83 1190/CHE/2013 Curcumin rubia skin glow method of preparation in lactose without March 20, 2013
the use of raw milk as a survivor to liver, hair, and skin glow
84 797/CHE/2013 A topical wound healing composition February 25, 2013
85 226/CHE/2013 Sustained release formulations of curcuminoids and method of January 17, 2013
preparation thereof
86 3424/DEL/2012 Design of curcumin loaded bionanoparticles for colon-specific November 6, 2012
drug delivery
(Continues)
16 BHAT ET AL.

TABLE 4 (Continued)

S no. Patent no. Title Date

87 3406/DEL/2012 “A novel potent 1,2,4-triazole-based antifungal compound” November 5, 2012
88 4128/CHE/2012 Formulation of curcumin with enhanced bioavailability of November 3, 2012
curcumin and method of preparation and treatment thereof
89 2349/MUMNP/2012 Oral care compositions October 5, 2012
90 8081/DELNP/2012 Gelatin, a curcumin drug carrier system September 17, 2012
91 8082/DELNP/2012 Casein, a novel curcumin drug carrier system September 17, 2012
92 3237/CHE/2012 Chitosan-based nanocomplex for sustained drug delivery August 7, 2012
93 6344/DELNP/2012 Synergistic effect of tocotrienols and curcumin July 18, 2012
94 2497/CHE/2012 A biphasic antioxidant entity and a process for its preparation June 25, 2012
95 1806/CHE/2012 Novel solid lipid microparticles of curcumin-soya lecithin complex May 8, 2012
96 1321/DEL/2012 “Profound effect of curcumin along with vitamin-c on malathion April 30, 2012
induced toxicity reduction”
97 1288/DEL/2012 “Curcumin proniosomal/niosomal formulation, method for its April 26, 2012
preparation and use thereof
98 903/DEL/2012 “Herbal composition for cancer diagnosis and prevention-internal March 27, 2012
use medicine”
99 2650/DELNP/2012 “Biocompatiable and biodegradable polymers form renewable March 27, 2012
natural polyphenols”
100 731/DEL/2012 “Novel curcumin-drug conjugates” March 14, 2012
101 138/DEL/2012 Curcumin coated superparamagnetic iron oxide nanoparticles for January 17, 2012
biomedical applications
102 7342/DELNP/2011 “Nutritional composition comprising curcuminoids and methods of September 23, 2011
manufacture”
103 6941/DELNP/2011 “Rolling bearing” September 12, 2011
104 6663/DELNP/2011 “Grease composition, grease-packed bearing, universal joint for September 1, 2011
propeller shaft, lubricating oil composition, and oil-impregnated
sintered bearing”
105 2353/CHE/2011 The art, method, manner, process, and system of preparation of July 11, 2011
curcumin loaded chitin nanogels for skin penetration
106 4629/DELNP/2011 “Composition for the use to treat Alzheimer's disease” June 16, 2011
107 1734/MUM/2011 “Ethosome compositions of curcumin for transdermal delivery” June 14, 2011
108 2415/KOLNP/2011 Use of nitrogen-containing curcumin analogs for the treatment of June 10, 2011
Alzheimer's disease
109 1487/MUM/2011 A water-soluble composition having enhanced bioavailability and May 16, 2011
process thereof
110 1023/DEL/2011 “A novel pharmaceutical formulation comprising triazole April 8, 2011
antifungal drugs and bioenhancers”
111 757/CHE/2011 Solid form of curcumin, process for the preparation and its March 14, 2011
pharmaceutical composition thereof
112 1080/CHENP/2011 “Feed for poultry and swine” February 16, 2011
113 337/DEL/2011 Process for preparing encapsulated curcumin nanoparticles and February 10, 2011
applications thereof.
114 378/MUM/2011 Antimicrobial composition February 10, 2011
115 217/MUMNP/2011 Niacin compositions for reduction of amyloid beta peptide 42 February 4, 2011
(abeta 42) production and for treatment of Alzheimer's disease
(ad)
(Continues)
BHAT ET AL. 17

TABLE 4 (Continued)

S no. Patent no. Title Date

116 228/DEL/2011 “Nutraceutical supplement for bone & joint health” February 1, 2011
117 184/CHE/2011 Method of management of blood sugar January 20, 2011
118 3538/MUM/2010 Curcumin monosulphate, its salts, process for synthesis thereof and December 24, 2010
treatment of cancer
119 1189/KOL/2010 A process for preparing curcumin encapsulated chitosan-alginate October 27, 2010
sponge useful for wound healing
120 3190/CHE/2010 Novel polymorphs and cocrystals of curcumin October 27, 2010
121 2335/DEL/2010 Topical curcumin formulation September 29, 2010
122 2553/MUM/2010 Pharmaceutical compositions of curcumin September 15, 2010
123 2348/MUM/2010 Hemostatic biosponge August 23, 2010
124 3068/KOLNP/2010 Soluble complexes of curcumin August 19, 2010
125 2356/CHE/2010 A pharmaceutical composition of reformulated turmeric extract August 16, 2010
and a method thereof
126 1840/DEL/2010 Nonfoaming anti precancer and antimicrobial herbal toothpaste and August 5, 2010
a process thereof.
127 1839/DEL/2010 Anti-precancer and antimicrobial herbal mouthwash and a process August 5, 2010
thereof.
128 1689/DEL/2010 An improved process for the preparation of bland turmeric powder July 20, 2010
with enhanced curcuminoids
129 999/CHE/2010 A synergistic composition and process thereof April 9, 2010
130 950/CHE/2010 Formulation of curcumin with enhanced bioavailability of April 5, 2010
curcumin and method of preparation and treatment thereof
131 164/KOL/2010 A novel water-soluble curcumin loaded nanoparticulate system for February 22, 2010
cancer therapy
132 163/MUMNP/2010 Compositions including androgen receptor degradation (ard) January 27, 2010
enhancers and methods of prophylactic or therapeutic treatment
of skin disorders and hair loss
133 1679/MUM/2009 Colon targeted drug delivery using a natural polymer (gum) from July 21, 2009
Moringa oleifera
134 1588/CHE/2009 Stop smoking formula enigma 2× July 6, 2009
135 3828/CHENP/2009 “Novel curcumin derivative” June 30, 2009
136 670/DEL/2009 “Preparation of curcumin nanoparticles and evaluation of their March 31, 2009
bio-efficacy”
137 646/CHE/2009 Curcuminoids and its metabolites for the application in allergic March 23, 2009
ocular/nasal conditions
138 405/DEL/2009 “A process for the preparation of water-soluble amino acid March 3, 2009
conjugates of curcumin”
139 314/DEL/2009 “A bioactive polysaccharide from turmeric (Curcuma longa) and a February 18, 2009
process for the preparation thereof”
140 129/CHE/2009 Antiseptic herbal soap composition January 21, 2009
141 2822/CHE/2008 An improved synthesis of curcumin November 17, 2008
142 8202/DELNP/2008 Curcumin synthesis September 29, 2008
143 3656/KOLNP/2008 Phospholipid complexes of curcumin having improved September 8, 2008
bioavailability
144 1668/MUM/2008 Improved solubility form of curcumin August 5, 2008
145 1853/DEL/2008 Novel nonstaining turmeric/curcumin topical formulation August 5, 2008
(Continues)
18 BHAT ET AL.

TABLE 4 (Continued)

S no. Patent no. Title Date

146 1827/DEL/2008 Curcumin nanoparticles and methods of producing the same July 31, 2008
147 1568/MUM/2008 Novel anticancer hydrazino derivatives of curcumin and process July 23, 2008
for preparation thereof
148 1416/MUM/2008 Novel synergistic antimalarial pharmaceutical composition July 7, 2008
149 1296/DEL/2008 “Novel curcumin formulation” May 28, 2008
150 725/KOL/2008 An improved method for extraction of curcumin using a unique April 15, 2008
heating model by microwave extraction
151 806/DEL/2008 A process for the preparation of photo-stable encapsulated March 28, 2008
curcumin colorant from turmeric (Curcuma longa)
152 353/DEL/2008 “Sustained release pharmaceutical compositions containing February 11, 2008
curcumin and beta-cyclodextrin”
153 2295/MUM/2007 A pharmaceutical composition containing turmeric November 21, 2007
154 2007/CHE/2007 A composition for curing diseases of bovids September 7, 2007
155 1107/CHE/2007 Cosmetic and dermatological composition and method of use May 28, 2007
thereof
156 3620/DELNP/2007 “Composition and method for facilitating the healing of May 15, 2007
nonhealing and slow-healing wounds and ulcerations”
157 995/DEL/2007 A process for the preparation of photo-stable, water-soluble May 8, 2007
curcumin from turmeric(Curcuma longa)
158 85/DEL/2007 A process for the preparation of antimicrobial coating for wound January 12, 2007
covering
159 1352/DEL/2006 “A recombinant antibody linked to drugs for killing of advanced June 6, 2006
stage cancer cells”
160 762/CHE/2006 An antioxidant composition, a process for preparation of an April 25, 2006
antioxidant-promoting composition and method of use thereof
161 493/CHE/2006 Composition for relief osteoarthritis, rheumatoid arthritis, cervical March 20, 2006
spondylosis, polyarthritis, and ankylosing spondylosis and
method of use thereof
162 1612/CHE/2005 “A combination of antimalarial drug therapy with curcumin and November 7, 2005
artemisinin”
163 756/DEL/2005 “An enzymatic process for the preparation of curcumin glycoside” March 31, 2005
164 786/DEL/2005 “An improved process for the preparation of tetrahydro curcumin” March 31, 2005
165 1184/DEL/2004 “A chemotherapeutic composition used in the treatment of cancer.” June 25, 2004
166 544/CHE/2004 Novel curcumin derivatives and use of curcumin and its June 11, 2004
derivatives as novel p300/cbp specific inhibitors of
acetyltransferase and therapeutic compositions thereof
167 562/DEL/2004 A process for the preparation of methyl ethers of curcuminoids March 22, 2004
168 256/CHE/2003 Curcuma pelletization March 24, 2003
169 215/DEL/2001 A process for the isolation of ar. Turmerone oil from turmeric February 28, 2001
oleoresin industry waste
170 1568/MUM/2008 Novel anticancer hydrazino derivatives of curcumin and process July 23, 2008
for preparation thereof
171 1416/MUM/2008 Novel synergistic antimalarial pharmaceutical composition July 7, 2008
172 1296/DEL/2008 “Novel curcumin formulation” May 28, 2008
173 725/KOL/2008 An improved method for extraction of curcumin using a unique April 15, 2008
heating model by microwave extraction
174 806/DEL/2008 A process for the preparation of photo-stable encapsulated March 28, 2008
curcumin colorant from turmeric (Curcuma longa)
BHAT ET AL. 19

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